Chapter 183: Benzodiazepines

Benzodiazepines, to varying degrees, have in common six major pharmacologic effects: sedative, hypnotic, anxiolytic, amnestic, anticonvulsant, and muscle relaxant.¹ Benzodiazepines are commonly used for the short-term treatment of anxiety, insomnia, seizures, and alcohol and sedative-hypnotic withdrawal.^2,3,4,5 The long-term benefits of benzodiazepines for psychiatric disorders are controversial.^6,7 Midazolam, a benzodiazepine with a short duration of action, is also used for procedural sedation and general anesthesia (Table 183–1).

Isolated benzodiazepine overdose has low mortality, and death is rare.⁸ However, increased rates of morbidity do result from mixed overdose, especially in combination with opioids. Isolated overdose with high-potency short-acting agents, such as alprazolam, temazepam, and triazolam, is associated with higher incidences of intensive care unit admissions, coma, and mechanical ventilation with toxicity compared to other benzodiazepines, such as diazepam.⁹ In the ED, parenteral administration of benzodiazepines may result in significant complications, particularly respiratory depression and hypotension, especially when combined with opioids or other sedatives.

Benzodiazepines stimulate the α subunit of the postsynaptic γ-aminobutyric acid (GABA_A) receptor in the CNS. Stimulation of this receptor affects the ligand-gated chloride channel on the cell membrane, altering the transmembrane resting potential to below stimulation threshold and rendering the postsynaptic neuron less excitable. Stimulation of this GABA_A receptor leads to inhibitory effects throughout the neuraxis, producing the typical clinical effects of sedation, anxiolysis, anticonvulsant activity, and striated muscle relaxation.

In general, benzodiazepines are well absorbed from the GI tract. The onset of action after oral ingestion is limited more by the rate of absorption from the GI tract than by the relatively rapid passage from the bloodstream into the brain. With the exception of lorazepam and midazolam, IM injection of benzodiazepines results in unpredictable absorption. IV administration of midazolam and lorazepam has an onset of action in 1 to 5 minutes. Diazepam may be administered rectally, and midazolam may be administered intranasally or intrabuccally, with variable rates of absorption by those routes.

Benzodiazepines are relatively lipid-soluble, with some variation among the agents. Increased lipid solubility is associated with more rapid diffusion across the blood–brain barrier. After single doses, the more highly lipophilic benzodiazepines have a shorter onset of action but also a shorter duration of activity. This short duration of activity occurs because of rapid egress of the drug from the brain and bloodstream into inactive tissue storage sites. For this reason, the serum half-life is not a good indicator of the duration of action in an acute ingestion.

Benzodiazepine derivatives undergo hepatic metabolism through different pathways depending on the agent. Hepatic biotransformation occurs through either oxidation or conjugation; both pathways may be used by some derivatives. Oxidation often produces active metabolites that prolong the pharmacologic effects of the parent compounds. Oxidation is more susceptible to impairment by such factors as disease states (chronic liver disease), demographic characteristics (advanced age), and concurrent treatment with drugs that affect metabolism (estrogen, isoniazid, ethanol, ketoconazole, cimetidine, and phenytoin). Conjugation is a rapid process that generally produces inactive metabolites. Examples of agents that undergo conjugation primarily include lorazepam, oxazepam, and temazepam. These agents may be safer in these susceptible groups such as those patients with hepatic dysfunction.

There is conflicting evidence on how benzodiazepines affect fetal development.^10,11,12 In general, the cohort studies did not find an increase in congenital malformations, but the case-control studies did show a small increase, especially for cleft lip and palate. This difference is ascribed to the higher sensitivity of case-control studies in identifying an association with specific conditions. The effect on fetal outcome of large doses of benzodiazepines taken for suicide attempts by pregnant women is not clear. Retrospective reviews of overdose with four different benzodiazepines, albeit with relatively small numbers, did not find an increased incidence of congenital abnormalities in the offspring.^13,14,15,16

Chronic use of benzodiazepines during pregnancy can result in withdrawal syndrome in the infant after birth such as "floppy baby syndrome" (sedation, hypotonia, apnea, cyanosis, hypothermia) and neonatal withdrawal (restlessness, hypertonia, tremors).¹⁷ Nearly all benzodiazepines enter breast milk, and therefore, caution should be exercised in patients taking benzodiazepines.^10,11

Administration of benzodiazepines in patients with comorbid conditions such as hepatic dysfunction or the elderly may cause significant effects. Those with hepatic dysfunction may have impaired metabolism, causing increased clinical effects. Elderly patients taking benzodiazepines are at increased risk for falls, cognitive impairment, delirium, fractures, and motor vehicle accidents.^12,18

Drug–drug interactions with benzodiazepines occur mainly with drugs that affect the cytochrome P450 pathway, specifically CYP3A4 and CYP2C19. For example, drugs such as ketoconazole or cimetidine are CYP3A4 inhibitors and may increase benzodiazepine blood levels, increasing their duration of action and/or clinical effect. Benzodiazepines themselves have not been implicated in affecting cytochrome P450 enzymes and, therefore, are unlikely to interfere with metabolism of other agents.

The clinical presentation of benzodiazepine intoxication is nonspecific and may be highly variable because of the frequent co-ingestion of other agents. Except for additive effects, drug interactions of benzodiazepines with other sedative-hypnotics are unusual.

The predominant manifestations of benzodiazepines are neurologic and are characterized by somnolence, dizziness, slurred speech, confusion, ataxia, incoordination, and general impairment of intellectual function. Prolonged coma is atypical and should prompt suspicion of intoxication with other agents or a non–toxin-related medical condition. In the elderly, infants and children, protein-deficient persons, and those with hepatic disease, the neurologic effects of benzodiazepines may be prolonged or enhanced.

Paradoxical reactions, including excitement, anxiety, aggression, hostile behavior, rage, and delirium, have been reported but are quite uncommon. Paradoxical reactions may occur more with hyperactive children and in psychiatric patients. Benzodiazepines may have a disinhibiting effect, which, in the presence of various extrinsic factors, can lead to such actions as aggressive or hostile behavior. Other effects that have been reported and that have unclear etiologies include headache, nausea, vomiting, chest pain, joint pain, diarrhea, and incontinence.

Benzodiazepines may cause short-term anterograde amnesia; this effect may be desired, especially in procedural sedation.¹² Agents most often associated with anterograde amnesia are lorazepam, midazolam, and triazolam, although this may occur with the other benzodiazepines.

Uncommonly, respiratory depression and hypotension may occur, generally with either parenteral administration or in the presence of co-ingestants. IV administration is more likely to cause serious cardiorespiratory effects with rapid administration of large doses. In addition, the elderly and those with underlying cardiorespiratory disease are more susceptible to adverse effects of IV administration.

Propylene glycol as a diluent in parenteral preparations of diazepam and lorazepam may cause severe metabolic acidosis (lactic acidosis), nephrotoxicity, and hyperosmolar states when infused at doses >1 milligram/kg per day for an extended period of time.^19,20 During such treatment, an osmolar gap >10 is predictive of elevated propylene glycol concentrations.²⁰ Treatment of propylene toxicity is generally supportive but may require hemodialysis.²¹

Extrapyramidal reactions have been associated with the use of midazolam. Various allergic, hepatotoxic, and hematologic reactions also have been reported, but they are infrequent. In general, benzodiazepines have no long-term organ-system toxicity other than that which can be ascribed to indirect effects from neurologic or cardiorespiratory depression.

Toxicologic testing in benzodiazepine ingestion is of limited value. Serum benzodiazepine levels do not correlate well with the clinical state, so serum level measurement is not routinely indicated. Qualitative testing with urine drug screens is typically designed to identify major metabolites of most benzodiazepines, such as oxazepam, temazepam, or nordiazepam, and not the parent compound.²² Depending on the antibody specificity used in the immunoassay, a false-negative test can occur and is commonly seen with midazolam and flunitrazepam. A urine benzodiazepine screen can usually detect a short-acting agent (e.g., lorazepam) up to 3 days and a long-acting agent (e.g., diazepam) up to 30 days after ingestion. Thus, detection of a benzodiazepine agent taken in the recent past may not correctly identify the toxicologic cause of the patient's current condition. False-positive benzodiazepine urine drug screens have been reported with oxaprozin and sertraline, although improved immunoassay techniques have reduced this potential interference.^23,24

GENERAL MEASURES

Benzodiazepines often are ingested with other agents, and the history is frequently inaccurate. Therefore, in patients with depressed or altered mental status, other metabolic and toxicologic possibilities should be considered (see chapter 176, General Management of Poisoned Patients). Do not induce emesis in benzodiazepine overdose because mental status depression may develop and increase the risk for pulmonary aspiration. Activated charcoal binds benzodiazepines effectively and may be considered. Gastric lavage, elimination enhancement by forced diuresis, hemodialysis, or hemoperfusion is not effective. Monitor neurologic and respiratory status and provide mechanical ventilation if necessary. Aspiration pneumonitis may be caused by severe respiratory and neurologic depression.

BENZODIAZEPINE ANTAGONIST

Flumazenil is a unique selective antagonist of the central effects of benzodiazepines, although there have been inconclusive claims that it may be effective in reversing the neurologic toxicity from other drugs.²⁵ Potential clinical applications include the reversal of coma in benzodiazepine overdose and reversal of iatrogenic benzodiazepine-induced sedation during procedural sedation.^22,26 Its use in benzodiazepine toxicity may obviate the need for tracheal intubation and respiratory support.²⁷

However, some toxicologists advocate that flumazenil has limited utility in the ED, noting it is useful mainly in reversing the effects of short-acting benzodiazepines administered for diagnostic and therapeutic procedures.²⁸ Even in such cases, management is usually accomplished safely and easily by allowing the effects of the benzodiazepine to subside without antidotal administration. Although the plasma elimination half-life of flumazenil is approximately 1 hour, its duration of action is variable and depends on the dose of flumazenil and the benzodiazepine administered. Recurrent benzodiazepine toxicity may result once the effects of flumazenil have worn off. This is less likely for a benzodiazepine with a short duration of action, such as midazolam. The dose of flumazenil is 0.2 milligram IV, which can be repeated every minute, titrated according to response or to a total dose of 3 milligrams.

Several considerations should limit the empiric administration of flumazenil to a poisoned patient (Table 183–2). There is a higher incidence of side effects, albeit generally minor, when flumazenil is administered to an unconscious patient presenting to the ED.²⁷ Of greater importance, generalized seizures have occurred in patients given flumazenil after co-ingestions of benzodiazepines and seizure-inducing agents, particularly cyclic antidepressants.²⁹ Seizure activity after flumazenil administration also has occurred in patients physically dependent on benzodiazepines and in patients receiving benzodiazepines for control of a seizure disorder. The putative explanation for this convulsive activity is either the reversal of the cerebroprotective and anticonvulsive effects of benzodiazepines or the precipitation of a benzodiazepine withdrawal syndrome.

Flumazenil-precipitated seizures in patients who are chronically taking benzodiazepines should be treated aggressively with another GABA_A receptor agonist because the benzodiazepine site on the receptor is antagonized. Anticonvulsants such as phenobarbital or propofol are recommended for flumazenil-induced seizures. Careful monitoring of the patient's respiratory and mental status is necessary during treatment and may require securing the airway.

Another reason to avoid empiric administration of flumazenil in overdose patients is that the history is often unreliable or unavailable. The apparent overdose may be caused instead by an intracranial mass lesion. Flumazenil is contraindicated in patients with a suspected elevation of intracranial pressure, such as in severe head injury, due to its adverse effect on cerebral hemodynamics.

Indications for observation or hospital admission include significant alterations in mental status, respiratory depression, and hypotension. If mental status depression persists or is profound, other agents or conditions must be considered. Although many clinicians use the 6-hour principle for observation of stable patients after ingestion, there is insufficient literature to recommend a specific duration for appropriate ED observation to conclude the patient is safe for discharge or transfer after a benzodiazepine overdose.

Physiologic addiction to benzodiazepines may occur, particularly with prolonged use and high doses.³⁰ Benzodiazepines are usually abused by individuals who abuse other psychoactive drugs and use the benzodiazepine to augment the effects of the primary agent or to counter its adverse effects. In addition, those with alcohol addiction may abuse benzodiazepines.

Benzodiazepine withdrawal may occur on abrupt discontinuation and is more likely in patients with prolonged use and high doses. Because of the long biologic half-life of several derivatives, withdrawal manifestations may not occur for several days to more than 1 week after discontinuing the benzodiazepine. Unfortunately, it is often difficult to distinguish between withdrawal and underlying symptoms for which the drugs were prescribed initially.

Reported withdrawal manifestations include anxiety, irritability, insomnia, nausea, vomiting, tremor, sweating, and anorexia. Serious manifestations, including confusion, disorientation, psychosis, and seizures, also have been reported. For patients with an acute organic brain syndrome, a history of possible benzodiazepine withdrawal always should be pursued. Withdrawal reactions may be avoided by gradually tapering the medication, although there is no consensus benzodiazepine tapering method, including the length of time to taper.^31,32 It appears that slow tapering over weeks to months may be preferred. Treatment of acute withdrawal reactions may be accomplished by drug substitution or by reintroduction of a benzodiazepine with subsequent tapering.³³ Benzodiazepine equivalent dosing should be considered if treatment with benzodiazepine substitution is performed. Withdrawal from high-potency benzodiazepines, such as alprazolam, may require higher doses of traditional benzodiazepines (e.g., IV diazepam) to achieve the appropriate clinical response.